Iron Deficiency

Iron deficiency anemia is the most common hematologic disease of infants and children. In the United States the prevalence has been declining since the 1960’s due to improved iron supplementation. In children, “normal” values vary with age, gender, and geographic location. Anemia due to decreased iron stores can be caused by inadequate intake, poor absorption, or blood loss. To maintain a positive iron balance in childhood about 1 mg of iron must be absorbed each day.

Anemia is defined a two standard deviations below the mean for age group. The AAP recommends screening for anemia between the ages of 9-12 months with additional screening between the ages of 1-5 years for patients at risk. Menstruating children should be screened annually. Should consider earlier screening for high-risk infants. Anemia seen during the first 2-3 months of life, known as physiologic anemia of infancy, is not due to iron deficiency and does not respond to iron therapy. In preterm infants, called anemia of prematurity, appears 1-2 months of age and is often more severe.

Epidemiology

The World Health Organization estimates that iron deficiency anemia affects approximately one-third of the population. The Centers for Disease Control and Prevention’s Pediatric Nutrition Surveillance system in Vermont showed that the prevalence of anemia between 1981 and 1994 fell from 7.9 to 3.6% in low income children aged 6 months to 5 years. The use of iron-fortified formula helps ensure adequate iron supplies for infants. However, toddlers often have diets that contain minimal amounts of iron-rich foods and large amounts of cow milk. The early introduction of whole cow milk before the age of 1 and consumption of greater than 24 oz of whole cow milk per day after the first year of life increases the risk of iron deficiency. Cow's milk is low in iron and interferes with iron absorption. In addition, cow's milk may cause gastrointestinal bleeding in some infants.  Data from the Third National Health and Nutrition Examination Survey indicated that 9% of children age 12-36 months in the US had iron deficiency and that 3% had iron deficiency anemia. There was a higher prevalence of iron deficiency among children living at or below the poverty level, among premature or low-birth-weight infants, among Afro-American and Mexican-American children, and among infants fed only non-iron fortified formulas. Adolescents are also susceptible to iron deficiency because of the high requirements due to growth spurt, dietary deficiencies, and menstrual blood loss. In the US about 9% of 1-2 year-old children are iron deficient; 3% have anemia. Of adolescent girls 9% are iron deficient and 2 % have anemia. In boys 50% decrease in stored iron occurs as puberty progresses.

Biology

Iron is absorbed from the gastrointestinal tract and transported in the blood bound to transferrin. Excess iron is stored primarily in the liver, bone marrow, and spleen as ferritin. Intestinal iron absorption is a function of three principal factors: body iron stores, erthropoietic rate, and bioavailability of dietary iron. Low iron stores increase receptors in the intestinal mucosa to facilitate increased iron uptake.

The developing fetus builds iron stores from maternal supplies, a normal term infant is born having sufficient iron stores for at least 4-6 months of postnatal growth. During the first few months of life, newborn uses iron at a high rate for accelerated growth and expansion of blood volume. By 4 months of age, in infants iron stores have decreased by 50%. The preterm infant has less time to accumulate iron in utero and is born with lower iron stores. The preterm infant has faster rate of postnatal growth than the term infant and may deplete iron stores within 2-3 months. During the first year of life, normal infants need to absorb approximately 0.8 mg/dL of dietary iron.

There are several conditions in the newborn period that can lead to early development of iron deficient anemia, these include: prematurity, the administration of erythropoietin for anemia of prematurity, fetal-maternal hemorrhage, twin-twin transfusion syndrome, other perinatal hemorrhagic events and insufficient dietary intake. Dietary issue that contribute significantly to the development of iron deficient anemia in infancy and childhood include: insufficient iron intake, decreased absorption due to poor dietary sources of iron, early introduction of whole cow’s milk, medications, and malabsorption states.

Blood loss must be considered as a possible cause in every iron-deficiency anemia, especially in older children and may be due to peptic ulcer, Meckel diverticulum, polyp, hemangioma, or inflammatory bowel disease. Some infants with severe iron deficiency have chronic intestinal blood loss induced by exposure to a heat-labile protein in whole cow’s milk.

The minimum daily requirements are 1mg/kg fro full-term infants started no later than fourth months in breast feed infants, 2mg/kg in premature infants started no later than two months in breastfeed infants, 3-4 mg/kg in very low birth weight infants started no later than two months in breastfeed infants, 10mg/day in 1-10 year old children, 15 mg/day in 11 year old to adult females, and 12mg/day in 11 year old to adult males.

Clinical presentation

Pallor is the most important sign of iron deficiency. The signs and symptoms of iron deficiency with and without anemia depend on the degree of deficiency and the rate at which the anemia develops. Children who have iron deficiency or mild-to-moderate anemia may show few, if any, signs or symptoms.  As the degree of anemia worsens, fatigue, exercise intolerance, tachycardia. Cardiac dilation, and systolic murmurs may develop. Infants and toddlers may demonstrate irritability and anorexia.  When the hemoglobin level falls below 5g/dL, irritability and anorexia are prominent.

Iron deficiency anemia in infancy and early childhood is associated with developmental delays and behavior disturbances that may be irreversible. Iron deficiency in infancy is associated with persistent changes in transmission through the auditory and visual systems, suggesting that myelination may be impaired.

Iron deficiency anemia is associated with poor growth and may produce other systemic abnormalities, such as blue sclera, koilonychias, angular stomatitis, increased susceptibility to infection, and functional alterations in the gastrointestinal tract. Iron deficiency increases lead absorption and has been associated with pica. Pagophagia, or pica for ice, is considered quite specific for iron-deficiency.

Evaluation/diagnosis

Dietary history alone may be suggestive of iron deficiency, but due to low specificity of dietary history for iron deficiency anemia, it cannot eliminate the need for further laboratory testing. If iron deficiency anemia is suspected a CBC, Hgb, Hct, smear and reticulocyte count is usually sufficient for screening for diagnosis. Further laboratory testing such as measurement of serum ferritin, will confirm diagnosis, but in most cases is not necessary. A more complete evaluation of iron deficiency anemia is indicated at presentation in children with complicated medical histories, which would include serum iron, ferritin, total iron-binding capacity, and transferring saturation.

With iron deficiency anemia Hbg <11 g/dL (decreased), MCV <70 (decreased), RDW > 15% (increased), reticulocyte count<1 (decreased), serum ferritin <10mcg/dL (decreased), serum iron <40 mcg/dL (decreased), total iron capacity>410 (increased), transferrin saturation <10 % (decreased), and serum transferring receptor >35nmol/L (increased).

Figure: Smear characteristic for iron deficiency. RBCs on the peripheral smear demonstrate an area of central pallor, which is normally 1/3 the diameter of the cell. Increased central pallor indicates hypochromic cells. (Image from Stanely Schier @ 2002 in ASH Image Bank 2002; doi:10.1182/ashimagebank-2002-100325.)

Treatment

For infants with presumptive diagnosis of iron deficient anemia a therapeutic trail of ferrous sulfate is diagnostic and therapeutic. Ferrous sulfate 3 mg/kg for four weeks should produce an increase of 1 g/dL or greater confirming the diagnosis of iron deficiency anemia. Ferrous sulfate should be continued 8 weeks after blood values are normal. An incorrect diagnosis of iron deficiency anemia may be revealed by therapeutic failure of iron medication. For infants with confirmed iron deficiency anemia, ferrous sulfate 3-4 mg/kg in divided doses in between meals with juice remains the standard of therapy.

Family should be educated about he patient’s diet, ad the consumption of cows milk should be limited to preferable 500mL (1 pint)/day or less. By doing this the amount of iron-rich food is increase, and blood loss from intolerance to cow’s milk is reduced.

Iron deficiency can be prevented in high-risk population by providing iron-fortified formula or cereals during infancy.

Long-term effects

Iron deficiency anemia in infancy and early childhood is associated with developmental delays and behavior disturbances that may be irreversible. Numerous studies have documented lower test scores of mental and motor development among infants who had iron deficiency. In some follow-up studies, test results normalized after treatment, but in others developmental delays persisted, despite treatment. The extent and persistence of brain involvement seem to depend on age at which the anemia first developed as well as its degree and duration

Follow-up

Regular follow-up is important to determine compliance with therapy and to assess for recurrence. After 1 month of therapy, the Hgb measurement should be repeated. If no improvement in Hgb should prompt further evaluation of the anemia with additional laboratory tests. Ferrous sulfate should be continued for 1-3 months after Hgb has returned to normal. Hgb should be remeasured approximately 6 months after discontinuation of ferrous sulfate.

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